PROJECT SUMMARY/ABSTRACT Fuchs' endothelial corneal dystrophy (FECD) is a leading cause of corneal blindness that affects females twice as often as males. Corneal transplantation is successful at restoring vision in FECD, but is limited by complications and availability of donor tissue in many parts of the world. The long term goal of this research is to develop drug therapies and preventive strategies for FECD to decrease the need for transplantation. Understanding the basis for the sex disparity in prevalence of FECD is necessary to develop effective alternative preventive and treatment strategies. The limited age and sex stratified data on FECD suggest that the incidence of FECD in females peaks in the postmenopausal age group while remaining stable in males. Because levels of serum estradiol change dramatically in women of this age group, the central hypothesis of this study is that estradiol protects the corneal endothelium via estrogen receptor beta (ER?). The postmenopausal decrease in estradiol leads to increased corneal endothelial metabolic stress that manifests as increased severity of FECD in females compared to males. The goal of this mentored career award to Sangita Patel, MD, PhD is to equip her with the skills necessary to lead epidemiologic and laboratory research on FECD. Dr. Patel's scientific expertise in physiology (MD, PhD, Physiology, Univ at Buffalo) and clinical expertise in cornea (ophthalmology residency, Mayo Clinic; cornea fellowship, Massachusetts Eye and Ear Infirmary) form the framework for an ideal leader for developing novel treatments for FECD. To successfully continue this path, Dr. Patel has three primary objectives for the K08 career development award: 1.To learn the principles of clinical and epidemiologic study design in order to effectively collaborate with epidemiologists to conduct validly designed studies; 2.To learn essential biostatistics for basic science and epidemiology research applications; and. 3.To build successful collaborative relationships in which she can lead with her clinical and scientific background. Key elements of the career development plan to address these objectives are: 1. Research skills development (epidemiology and biostatistics) through didactics and practical application; 2. Publications, presentations, and initiation of collaborative studies with support by her mentoring team (leaders in ophthalmic research and epidemiology); and 3. Submission of a NIH R01 application as an independent investigator in Year 4. She will undertake these activities in the diverse, stimulating collaborative environment at the University at Buffalo. The Specific Aims of this application are designed to test the central hypothesis and encompass the career development goals. Specific Aim 1 is to determine the effect of age on the sex disparity of FECD prevalence and to evaluate the association between estrogen exposure and FECD severity. Specific Aim 2 is to determine the roles of estradiol and ER? in regulating the response to oxidative stress in the corneal endothelium. The outcomes of these studies will provide the scientific and clinical epidemiologic data to support significant future advances toward targeting estradiol pathways for FECD therapeutics.